2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Olanzapine) is an atypical neuroleptic agent that has better reported efficacy and few side effects than conventional neuroleptic agents. It is useful in the treatment of psychotic patients and mild anxiety states.
U.S. Pat. No. 5,229,382 and its Continuation-In-Part application, now U.S. Pat. No. 6,008,216 to Chakrabarti, et. al., disclose processes for Olanzapine preparation by different intermediates. One of the known procedures consists of reduction and cyclization reaction of 2-(2-nitroanilino)-5-methylthiophen-3-carbonitrile with stannous chloride (SnCl2) in an aqueous-alcoholic solution of hydrogen chloride followed by a reaction of thus formed 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine [3] with N-methylpiperazine in an organic solvent or solvents mixture such as anisole, toluene, dimethylformamide or dimethylsulphoxide, preferably at a temperature from 100° to 150° C. for about 20 hrs, to which alcohol and excess water is added after the reaction is complete (Scheme A). The crude product is separated out and collected. The crude Olanzapine is then crystallized in acetonitrile and gives a crystalline form, which is designated as Form I in later patents.
In PCT applications numbered WO 02/18390 and WO 03/097650, it has been disclosed that Polymorphic Form II of Olanzapine with XRD starting from 10.26 is obtained by following the procedure disclosed in U.S. Pat. No. '382, more particularly the process disclosed in the Example 1 Sub-Example 4 for the crystallization of Olanzapine in acetonitrile,

Another of the known procedure consists cyclization of 1-{[2-(2-aminoanilino)-5-methylthiophen-3-yl]carbonyl}-4-methylpiperazine (9), using titanium tetrachloride as catalyst and anisole as solvent at reflux temperature in 48 hours. The long reaction time yields multifold impurity profile and thus low productivity. The product was purified by chromatography on florisil by using ethyl acetate. The separation through chromatography is not desirable and therefore this method is not suitable for large-scale manufacturing. The product with the formula [9] is prepared in situ by reacting a compound of formula [7] with N-methyl piperazine at 100° C. in a solvent such as anisole and employing titanium chloride as a catalyst. The amino ester [7] is prepared from the reduction of corresponding nitro ester [6] e.g. by employing hydrogen and palladium/carbon in ethanol and ethyl acetate mixture or stannous chloride and hydrogen chloride in aqueous ethanol. The nitro ester can be made by condensation of thiophene with an ortho-halonitrobenzene, preferably ortho fluoro- or chloro-nitrobenzene in the presence of base, for example (a) sodium hydride in tetrahydrofuran or (b) anhydrous potassium carbonate or lithium hydroxide in dimethlysulphoxide. This reaction takes 20 hours to complete. This process is depicted in Scheme B. The reaction yields of the prior art processes are low (˜30%) as all the steps take long hours to complete.

In international application no. WO 2004/00847, Olanzapine is prepared by the N-methylation of N-desmethylolanzapine with formaldehyde in presence of reducing agent e.g. borohydride of group I or II metal or of alkali metal and acetic acid in aqueous media or formic acid or by hydrogenation in presence of metal catalyst. In another process N-methylation of N-desmethylolanzapine is carried out by ethyl formate. In another process the said N-methylation is carried out by direct methylation of N-desmethylolanzapine with a methylating agent e.g. methyl iodide.
In most of the prior art methods technical grade Olanzapine is separated in the form of solvate with alcohol. Depending on the solvent used for the crystallization of technical grade Olanzapine, different polymorphic forms are obtained by different prior art methods.
Olanzapine is found in different polymorphic forms and most of the prior arts describe different conditions and solvents for the preparation of these polymorphic forms. Polymorphism can be influenced by controlling the conditions of obtaining a compound in solid form. These polymorphic forms are distinguished on the basis of IR and X-Ray diffraction data.
Attempts to reproduce the methods known in the prior art for isolation and purification of Olanzapine, obtained by the condensation of N-methylpiperazine and 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine in organic solvent, e.g. dimethylsulphoxide and/or toluene, and subsequent addition of water and alcohol, show that obtained product contains high percentage of impurities and recovery of different solvents is difficult and thus not industrially feasible. The boiling point of dimethylsulfoxide is 189° C. The boiling point of the other solvent toluene, which is used as a co-solvent with DMSO, in most of the prior arts, is 110° C. Thus it is rather difficult to remove these solvents by conventional methods. The reaction takes 20-22 hours to complete. This long reaction time decreases the manufacturing capacity.
Other drawback of the prior art is the use of different solvents at different stages of the process. The main solvent is Dimethylsulfoxide (DMSO), which penetrates to places in the body very swiftly. Dimethylsulfoxide substitutes for water and moves rapidly through cell membranes. It has been called “water's alter ego.” It changes the water structure within the cell. Thus the use of dimethyl sulfoxide is not desirable at the manufacturing level.
The present invention provides an improved process, which overcomes the drawbacks of processes recited in prior arts. The main aim of this invention is to provide a new improved and concise process for the large-scale production of Olanzapine.
Further aim of the present invention is to develop a process for production of Olanzapine, which will involve more simple and economical chemical steps, while allowing obtaining high yields of the final product having high purity by environment friendly process.